Methylenedioxymethamphetamine (MDMA) and methylenedioxyamphetamine (MDA) are both schedule 1 controlled substances with abuse potential as hallucinogens. The ready demethylation of most xenobiotics would suggest that MDMA is a prodrug and rapidly converted to its active form, MDA, by metabolism. However, some differences in pharmacological effects have been noted that suggest the two compounds are pharmacologically distinct. This project evaluates this notion and investigates the mechanism for the neurotoxicity of MDA by a study of the metabolism, neurochemistry and neurotoxicity of MDA and MDMA. The methylenedioxyphenyl function is the focus of the research since it could be responsible for inhibition of monooxygenase catalyzed metabolism, affinity for the 5HT neuron and formation of potentially toxic intermediates. The interaction of MDA and MDMA with cytochrome P450 will be determined from metabolic reactions and spectroscopic analysis. The affinities of the two compounds for catecholaminergic and serotonergic nerve terminals will be determined in vitro using synaptosome preparations and in vivo with voltammetry. The mechanism of neurotoxicity of the compounds will be determined by biochemical and histological procedures.